Injectable liquid formulation of paracetamol

ABSTRACT

The invention relates to a novel injectable liquid formulation of paracetamol, comprising an aqueous solvent, a buffer agent with a pKa between 4.5 and 6.5, an isotonic agent and the dimer of paracetamol of formula (I), a method for preparation of said formulation and the use of said dimer for the stabilisation of a liquid paracetamol pharmaceutical formulation.

The present invention relates to a novel injectable liquidpharmaceutical formulation of paracetamol containing a dimer of thisactive principle, to a process for preparing this formulation, and tothe use of this dimer for stabilizing a liquid pharmaceuticalformulation of paracetamol.

Paracetamol (INN of acetaminophen or N-(4-hydroxy-phenyl)acetamide) isan analgesic and an antipyretic widely used in hospitals. It isdesirable to have available stable liquid pharmaceutical formulations ofthis active principle for administration by injection, in particular forintravenous infusion.

It is known that paracetamol in aqueous solution is liable to undergohydrolysis to form p-aminophenol, which is itself liable to degrade intoquinoneimine (cf. for example J. E. Fairbrother, “Acetaminophen” inAnalytical Profiles of Drug Substances, 1974, vol. 3, pp. 1-109). Therate of degradation of paracetamol increases with increasing temperatureand light. This rate is minimal at a pH in the region of 6 (K. T. Koshyet al., 1961, J. Pharm. Sci. 50, pp. 116-118).

It is known practice to add a buffer and an antioxidant or free-radicalscavenger to stabilize paracetamol in solution.

WO 02/072 080, for example, describes stable aqueous paracetamolsolutions for infusion comprising a buffer of pH 5.5 to 6.5 and anantioxidant chosen from ascorbic acid and a derivative bearing a thiolfunction such as cysteine or acetyl-cysteine.

EP 0 916 347 discloses-paracetamol solutions based on a mixture of waterand of alcoholic solvents comprising a buffer of pH 5.5 to 5.6 andmetabisulfite as antioxidant.

The prior-art stabilized injectable solutions of paracetamol have thedrawback of causing a potential irritant, allergenic and/or carcinogeniceffect in certain patients, on account of the toxicity of theantioxidant they contain. Furthermore, their stability requires theremoval of the oxygen and other oxidizing agents from the aqueousmedium. These solutions therefore cannot be stored in plastic containersthat are partially permeable to oxygen or that comprise traces ofoxidizing residues.

The as yet unpublished patent application MI2001A002135 discloses stableinjectable aqueous solutions of paracetamol obtained by mixingparacetamol with water, propylene glycol and a citrate buffer, heatingthe solution obtained to a temperature of between 70 and 130° C. andmaintaining this solution at this temperature for at least 10 minutes.These solutions do not contain any toxic antioxidant, citric acid beinga weak antioxidant widely used in the food industry.

D. W. Potter et al., 1985, J. Biol. Chem. 260, 22, pp. 12174-80 disclosethe oxidation and polymerization of paracetamol in aqueous solution withhydrogen peroxide in the presence of horseradish peroxidase, isolationby semipreparative HPLC and identification by mass spectrometry and NMRspectroscopy, of two dimers, two trimers and two tetramers ofparacetamol. For a paracetamol concentration of greater than 0.2 mM, thedimer of formula (I) (“compound B”) is largely predominant.

The problem or aim of the invention is that of finding a novelinjectable liquid pharmaceutical formulation of paracetamol that isstable for a prolonged period without having the drawbacks mentionedabove.

This problem is solved by the invention as defined by the attachedclaims.

The invention relates to an injectable liquid pharmaceutical formulationof paracetamol that contains paracetamol, an aqueous solvent, a bufferwith a pKa of between 4.5 and 6.5, an isotonic agent and paracetamoldimer of formula (I).

This paracetamol dimer, even in very small amount, appears to act as anantioxidant and makes it possible to dispense with the strong or toxicantioxidants described for the prior-art stabilized solutions ofparacetamol.

The formulation of the invention has excellent stability at roomtemperature, and even at a temperature of the order of 40° C., and maybe stored in a plastic container, in particular an infusion bag, forexample a bag made of polypropylene, polyethylene, polyvinyl chloride orcombinations of extruded polymers.

This paracetamol dimer may be replaced with another paracetamolpolymerization product, for example a mixture of at least two oligomersof paracetamol chosen from the two dimers, the two trimers and the twotetramers of paracetamol described by D. W. Potter et al., 1985 in thereference cited hereinabove.

In general, this formulation contains at least 0.005% and preferably atleast 0.05%, as a ratio of the surface area of the HPLC peaks withdetection at 245 nm, of paracetamol dimer of formula (I).

The formulation of the invention may contain from 0.1 to 5.0 g/100 mland preferably from 0.4 to 1.5 g/100 ml of paracetamol.

The aqueous solvent is water, of injectable grade, or a mixture of waterand of one or more other water-miscible solvent(s), for examplepropylene glycol, polyethylene glycol, ethanol, and/or surfactants suchas polysorbates or poloxamers. If the desired content of paracetamol inthe solution exceeds 1.0 g/100 ml, the aqueous solvent will preferablybe a mixture of water and of water-miscible solvent(s).

The formulation of the invention contains a buffer with a pKa of between4.5 and 6.5 and preferably between 5.0 and 6.2. This buffer willadvantageously be chosen from citrate buffer, phosphate buffer,phosphate-citrate buffer, bicarbonate buffer, tartrate buffer andacetate buffer, preferably from citrate buffer, phosphate buffer andphosphate-citrate buffer, or a mixture of these buffers.

This formulation for injection contains an isotonic agent, intended tocreate an osmotic pressure in the region of that of physiologicalsaline. This isotonic agent is generally chosen from sodium chloride andglucose.

The formulation of the invention is generally prepared by first mixingtogether paracetamol, injectable-grade water, optionally one or moreother water-miscible solvent(s), and/or surfactants, buffer and isotonicagent, followed by heating the solution obtained, in bulk or prefilledin containers, at a temperature of at least 70° C. for at least 15minutes. The aim of this heating is to remove any trace of nucleationthat might trigger recrystallization of the paracetamol during thestorage of the solution.

The invention also relates to a process for preparing the formulationdefined above, which includes the mixing of paracetamol, water,optionally water-miscible solvent, and/or surfactants, buffer andisotonic agent, followed by heating of the solution obtained, in bulk orprefilled in containers, at a temperature of at least 70° C. for atleast 15 minutes.

The dimer of formula (I) appears to form spontaneously but slowly duringthe storage of the solution obtained above at a sufficient temperature,for example 60° C.

To form the dimer of formula (I) in situ, it is practical to heat thesolution at a temperature of between 100 and 130° C. and preferablybetween 110 and 125° C. for a period of at least 5 minutes.

The invention also relates to a process for preparing the formulationdefined above, which includes the heating of the solution at atemperature of between 100 and 130° C. and preferably between 110 and125° C. for a period of at least 5 minutes.

The invention also relates to a formulation as defined above that may beobtained via this process.

The invention also relates to the use of the dimer of formula (I) forstabilizing a liquid formulation of paracetamol. This dimer is generallymanufactured in situ within the liquid formulation of paracetamol.

The invention is described in greater detail in the examples below,which are given as nonlimiting illustrations.

In these examples, the temperature is room temperature or is expressedin degrees Celsius, and the pressure is atmospheric pressure. The water,the propylene glycol and all the reagents used are of injectable grade.

Moreover, all the examples form an integral part of the invention, asdoes any characteristic of the description including the examples, whichappears to be novel with respect to any prior art, in the form of ageneral characteristic rather than of a particular characteristic of theexample.

EXAMPLE 1 Preparation of Liquid Pharmaceutical Formulations According tothe Invention and Analysis of These Formulations by HPLC

Formulations 001, 002, 003, 004, 005 and 006 were prepared by mixingtogether paracetamol, ultrapurified injectable-grade water, optionally(formulation 004) propylene glycol, buffer (phosphate buffer,citrate-phosphate buffer or citrate buffer) and isotonic agent (sodiumchloride), heating at 70-90° C. for about 15 minutes to avoid thepossibility of nucleation and consequent recrystallization of theparacetamol, and filling of glass bottles. These bottles were thensterilized for 15 minutes at 121° C.

The solutions were analyzed, before and after sterilization, by HPLC ona column of octylsilyl silica gel and a mobile phase obtained by mixingtogether a solution of disodium hydrogen phosphate, a solution of sodiumdihydrogen phosphate and methanol R containing a solution oftetrabutylammonium R, and detection by spectrophotometry at 245 nm,according to the method recommended in the European Pharmacopoeia(European Pharmacopoeia 4.4, pp. 3503-4, 04/2003: 0049 Paracetamol).

A peak corresponding to an unknown substance (not accounted for by theEuropean Pharmacopoeia) was detected. This substance was identified, bymass spectrometry coupled to liquid chromatography (LC-MS) and protonnuclear magnetic resonance (NMR) at 200 MHz, as being the paracetamoldimer of formula (I), which is identical to compound B described by D.W. Potter et al., 1985, J. Biol. Chem. 260, 22, pp. 12174-80.

The detection limit is about 0.005% for p-aminophenol and the dimer offormula (I). The difference between 100 and the paracetamol valuemeasured is not significant and represents experimental uncertainty.

The compositions of these formulations and the HPLC analysis results arecollated in table 1 below. TABLE 1 Formulation 001 002 003 004 005 006Paracetamol (g/100 ml) 1.0 1.0 1.0 1.0 1.0 1.0 Propylene glycol (g/100ml) — — — 0.8 — — Monosodium phosphate dihydrate (g/100 ml) 0.10020.1071 0.0467 — — — Disodium phosphate dihydrate (g/100 ml) 0.0785 —0.0899 0.0877 — 0.091 Citric acid monohydrate (g/100 ml) — — — 0.04990.033 0.045 Sodium citrate dihydrate — — — — 0.131 — Sodium chloride(g/100 ml) 0.65 0.65 0.7 0.6 0.65 0.675 Water for injection to 100 ml to100 ml to 100 ml to 100 ml to 100 ml to 100 ml pH 5.7 4.7 6.9 5.2 5.35.4 Osmolality (mosm/kg) 284 290 307 290 287 296 HPLC analysis % dimer(before sterilization) * nd nd nd nd nd nd % paracetamol (beforesterilization) 100.8 100.2 99.1 99.1 99.3 98.2 % p-aminophenol (beforesterilization) nd nd nd nd nd nd % dimer (after sterilization) * 0.070.02 0.12 0.04 0.05 0.08 % paracetamol (after sterilization) 100.7 100.798.5 98.6 99.1 98.6 % p-aminophenol (after sterilization) nd nd nd nd ndnd* ratio of surface area of the peak for the dimer/surface area of thepeak for paracetamol, in %nd: not detected

For these formulations, a content of the dimer of formula (I) of from0.02 to 0.12 after sterilization was measured, this dimer not beingdetectable before the sterilization. The presence of p-aminophenol wasnot detected before or after sterilization.

EXAMPLE 2 Study of the Formation of the Dimer

1) Effect of Temperature and Time

The effect of the temperature on the formation of the dimer of formula(I) was studied on formulation 001 of example 1 after heating at 70-90°C. for 15 minutes and placing it in a glass bottle. This formulation wassubjected to various storage temperatures and/or to varioussterilization times, and analyzed by HPLC as described above in example1.

The main results are collated in table 2 below. TABLE 2 Effect oftemperature and time on the formation of the dimer p- ParacetamolAminophenol Dimer (%) (%) (%) Stored for 1 h at 70° C. 100.8 notdetected not (without sterilization) detected Stored for 14 days at100.2 not detected 0.10 60° C. (without sterilization) Sterilized for 10minutes 99.9 not detected 0.09 at 121° C. Sterilized for 20 minutes 99.7not detected 0.18 at 121° C. Stored at 40° C. for 100.4 not detected 0.414 days, after sterilization for 15 minutes at 121° C.

According to the above table, the dimer forms rapidly at 121° C., with arate of formation proportional to the sterilization time, and slowly butin measurable amount at 60° C. for 14 days. The dimer is not detectableafter one hour at 70° C.

p-Aminophenol is not detected under any of the conditions studied.

2) Effect of the pH

The values for the content of dimer of formula (I) given in table 1 ofexample 1 for formulations 001, 002 and 003 of compositions that aresimilar but with different pHs show that the formation of the dimerdepends on the pH. The more basic the pH, the larger the amount of dimerformed. The generation of the radicals is probably facilitated by theformation of the phenoxides.

EXAMPLE 3 Stability Study

The stability was studied on formulation 001 of example 1 after heatingat 70-90° C. for 15 minutes, put in glass bottles or polypropyleneinfusion containers, and sterilization at 121° C. for 15 minutes for theglass bottles and at 120° C. for 20 minutes for the polypropylenecontainers.

Table 3 below collates the results obtained by HPLC analysis asdescribed in example 1 above. TABLE 3 Stability of formulation 001 100ml polypro- 50 ml glass bottle pylene container 10 months 10 monthsStart 25° C. 40° C. Start 25° C. 40° C. Osmolality 283 288 285 281 289283 (mosm/kg) Paracetamol 100.3 100.7 99.1 100.3 100.4 99.4 content (%)Dimer content 0.11 0.23 0.73 0.09 0.14 0.47 (%) p-Aminophenol nd nd ndnd nd nd content (%) pH 5.6 5.6 5.6 5.6 5.6 5.6nd: not detected

This table shows that the injectable liquid formulation according to theinvention maintains the same paracetamol content after storage for 10months at 25° C. or 40° C., with a slight increase in the dimer content,which is higher at 40° C. than at 25° C., and higher in the glassbottles than in the polypropylene containers.

The degradation of paracetamol in solution is often studied by measuringthe absorbances at 500 nm according to the method described by J. E.Fairbrother “Acetaminophen”, in Analytical Profiles of Drug Substances,1974, vol. 3, pp. 1-109. Monitoring for three weeks, according to thismethod, of the absorbance firstly of formulation 001 and secondly of thecommercial formulation Perfalgan® containing 1.0 g/100 ml of paracetamoland cysteine hydrochloride, obtained as described in WO 98/05314, showsthat, at 60° C., paracetamol degrades at least ten times more quickly inthe Perfalgan® formulation than in the formulation of the invention.

1. An injectable liquid pharmaceutical formulation of paracetamol, whichcontains paracetamol, an aqueous solvent, a buffer with a pKa of between4.5 and 6.5, an isotonic agent and paracetamol dimer of formula (I)below:


2. The formulation as claimed in claim 1, which contains at least 0.005%and preferably at least 0.05%, as a ratio of the surface area of theHPLC peaks with detection at 245 nm, of paracetamol dimer of formula(I).
 3. The formulation as claimed in claim 1, which contains from 0.1to 5.0 g/100 ml and preferably from 0.4 to 1.5 g/100 ml of paracetamol.4. The formulation as claimed in claim 1, which contains a buffer chosenfrom citrate buffer, phosphate buffer, phosphate-citrate buffer,bicarbonate buffer, tartrate buffer and acetate buffer, preferably fromcitrate buffer, phosphate buffer and phosphate-citrate buffer, or amixture of these buffers.
 5. The formulation as claimed in claim 1,which may be obtained via a process including heating of the solution ata temperature of between 100 and 130° C. and preferably between 110 and125° C. for a period of at least 5 minutes.
 6. The formulation asclaimed in claim 1, in which the dimer of formula (I) is replaced withanother paracetamol polymerization product.
 7. A process for preparing aformulation as claimed in claim 1, which includes mixing togetherparacetamol, water, optionally one or more water-miscible solvent(s),and/or surfactants, buffer and isotonic agent, followed by heating thesolution obtained, in bulk or prefilled in containers, at a temperatureof at least 70° C. for at least 15 minutes.
 8. The process as claimed inclaim 7, which includes heating the solution at a temperature of between100 and 130° C. and preferably between 110 and 125° C. for a period ofat least 5 minutes.
 9. A glass or plastic container, in particular aninfusion bag, containing a formulation as claimed in claim
 1. 10. Methodof stabilizing a liquid formulation of paracetamol comprising providingthe dimer of formula (I) to the formulation.